The last few weeks has led to an outbreak of CARS (Confused Adult Respiratory Syndrome) over the index case of SARS in Guangzhou for this season, and the reported "full recovery" of the patient, suggests that he may have indeed have had MARS (Mild Adult Respiratory Syndrome) although an earlier respiratory illness in March and lack of an epi-link has led to speculation that he had SCRS (Severe Chronic Respiratory Syndrome), which progressed to MARS.
The novel sequence of the SARS CoV has implicated a new lineage, but all of the above, combined with animal sequence data of SARS CoVs and high frequencies of SARS CoV antibodies (in the absence of clinical disease) in market workers, especially those that handle masked palm civets, has led to a culling of civets and related market animals, which has led to concerns over destroying the evidence.
I think that the evidence is beginning to paint the following picture:
SARS CoVs are novel coronavirus that were not know to the scientific or medical community prior to the SARS outbreak last spring. However, the promiscuous virus has been infecting wild animals for some time and the infections are most prevalent in masked palm civets. The virus can easily pass from the civets to other animals, especially those housed together in open markets, as well as those who sell, slaughter, or cook related animals. This has led to a fairly significant viral gene pool, the mutates frequently. However, prior to last season, these mutations did not produce significant clinical symptoms.
Several variants emerged last season. Although the index case developed symptoms in Nov 2002, the epidemic didn't really take off until January 2003. At that time there were several animal to human jumps, leading to clinical manifestations. However, reports indicate that there were only 5 fatalities in the first 305 cases in Guangdong Province.
The disease then burst onto the International scene following the transmission at the Metrople Hotel, which was designated as a super spreader event. Additional super spreader event, the Prince of Wales outbreak, led to the Amoy Gardens outbreak and the Flight CA-112 outbreak, which then spread SARS to Taiwan and several cities in Mainland China.
Sequencing of the isolated virus indicated that the virus had about 4 dozen mutations relative to the civet sequences and these 4 dozen mutations were found in almost all human sequences, which now exceed 150.
However, the current database of sequences was generated using a heavy selection pressure. Most of the isolates grew in culture and caused SARS that was either fatal, highly contagious, or both. Missing from the database would be SARS CoVs causing milder infections (MARS) as well as those that did not grow well in culture. The BJ302 series from Beijing showed that many novel Spike gene mutations could be found with PCR screening. Although these mutations were found in many Beijing patients, they have not been reported in any isolated virus or in any clinical sample from patients outside of Beijing.
Thus, the possibility that SARS CoVs can cause a broad range of respiratory illnesses has not been thoroughly investigated. The recent heightened vigilance however, has led to the discovery of a novel SARS case. The novel S gene sequence only has 98.8% to 99.4% homology with previously sequenced SARS CoVs (although this frequency may be higher when compared to animal SARS CoVs) and the virus appears to represent a new animal to human jump.
The new jump is consistent with last season's outbreak, which can be seen in the sequences of the three masked palm civet isolates on deposit at GenBank. These three isolates have 19 polymorphisms which are found in all civet sequences but no human sequences, significantly reducing the chance that they are due to a human to civet transmission. However, additional polymorphisms suggest that the civets have some mutations that appear in all or most human isolates, even though the changes are not found in other civets.
These civet polymorphisms define some of the key molecular markers.
One civet (SZ16) has a marker found just in the raccoon dog sequence (SZ13) suggesting that the racoon dog was infected by the civet. Another civet, SZ1, has a marker that is found in almost all human isolates. It is missing in only the earliest human isolates, suggesting that this marker was introduced at a slightly later date. A third civet (SZ3) has a number of informative markers. It has four changes that are in all human isolates, indicating that these changes happened very early and became extremely well established. It also has two markers found just in one human isolate, GZ43, from an early transmission to a health care worker. SZ3 also has another marker found in CUHK-AG3, a fatal Amoy Gardens case.
Media reports suggest that the latest infection in Guangzhou involves yet another lineage which is closely related to yet another animal isolates. A number of additional animal isolates display various degrees of "humanization", similar to the shared markers described above.
Thus, the following picture is beginning to emerge. There are many SARS CoVs in wild animals in Guangdong Province. These isolates can produce a broad spectrum of human respiratory diseases. As the virus mutates further, infection and mortality rates can increase. Not all of these animal isolates grow well in culture and not all are easily detected with existing diagnostic probes and these novel isolates may not produce high titers in humans.
Using clinical parameters to detect the infections selects for the more mutated versions that produce higher infection rates and mortality. Thus, there may be large numbers of people with SARS CoV infections, who are asymptomatic (such as market workers), have mild respiratory symptoms, have mild SARS symptoms, or have full blown SARS. At this stage of the season, SARS, as seen in February, March, and April of last year, may not have emerged yet. Instead the initial animal jumps are producing a milder disease, not easily detected using classical SARS clinical criteria. There may be many cases of SARS CoV infections in cases with relatively mild conditions, but most of these individuals are not detected because they are not being screened.
Thus, at this time of year, SARS CoV infections may be quite prevalent, but full blown SARS is still quite rare. The current screening approaches do not address the spread of SARS CoVs. Instead the focus is on full blown SARS, so much of the SARS CoV evidence in humans is not being identified or analyzed. |
